The clinical efficacy, toxicity, and immunological effects of the newer adenosine analogs, such as fludarabine are being studied in patients with autoimmune rheumatic disorders in phase I/II clinical studies. These agents primarily affect lymphoid cells because these cells contain an enzyme necessary for activation of these compounds. Previous investigations employing these drugs in patients with low grade lymphoid malignancies have shown that they selectively target immune cells by inducing a physiologic form of cell death called apoptosis. Their effects on the clinical course of immunologic diseases, as well as on the function of immune cells have not been characterized. Twelve patients have been entered into a study for treatment of refractory rheumatoid arthritis and one into a study for the treatment of psoriatic arthritis. To date, no major or unexpected toxicities have been encountered. Fludarabine treatment has resulted in sustained B and T lymphopenia (B>T). We are attempting to determine whether the level of lymphopenia should be a major determinant of safe drug doses; no substantive changes in total immunoglobulin or antibody levels have been seen. At the low doses of fludarabine used, significant clinical effects have been observed in eight patients with rheumatoid arthritis who have completed this therapy so far.